1. Field of the Invention
This invention relates to 2-(1'-azabicyclo[2.2.2]oct-3'S-yl)-6-hydroxy-2,4,5,6-tetrahydro-1-H-benz[d e]isoquinolin-1-one and 2-(1'-azabicyclo[2.2.2]oct-3'S-yl)-6-hydroxy-2,3,3a,4,5,6-hexahydro-1H-ben z[de]isoquinolin-1-one and their individual stereoisomers and uses and the processes for their making.
2. Description of the Invention
Serotonin, a neurotransmitter with mixed and complex pharmacological characteristics, was first discovered in 1948 and subsequently has been the subject of substantial research. Serotonin, also referred to as 5-hydroxytryptamine (5-HT), acts both centrally and peripherally on discrete 5-HT receptors. The 5-HT receptor is presently delineated into four major subclassifications--5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3 and 5-HT.sub.4 receptors--each of which may also be heterogeneous. Receptors of the 5-HT.sub.3 subclass pervade autonomic neurons and appear to regulate the release of a variety of neurotransmitters in the gastrointestinal, cardiovascular and central nervous systems.
5-HT.sub.3 receptors are located in high densities on neurons associated with the emetic reflex and drugs which block the interactions of serotonin at the 5-HT.sub.3 receptor level, i.e., 5-HT.sub.3 receptor antagonists, possess potent antiemetic properties. Such antagonists demonstrate utility for counteracting the emetic effects of cancer chemotherapy and radiotherapy (see Drugs Acting on 5-Hydroxytryptamine Receptores: The Lancet Sep. 23, 1989 and references cited therein).
Functional bowel disorders are prevalent in much of the industrialized world. Chronic gastroesophageal reflux disease alone may be present in as much as 15% of the population. Use of prokinetic agents is one of the most effective methods known for treating such disorders. Because many 5-HT.sub.3 antagonists possess prokinetic properties and are relatively free form side effects they are particularly useful in the treatment of gastrointestinal disease (see Reynolds R. C. Prokinetic Agents: A Key in the Future of Gastroenterology. Gastroenterology Clinics of North America 1989; 18:437-457).
5-HT.sub.3 receptors are present in those areas of the brain which control mood, emotion, reward and memory. 5-HT.sub.3 receptor antagonists reduce mesolimbic dopamine levels, a necessary property for antipsychotic activity. Such antagonists also increase cholinergic tone in the limbic-cortical region, which may explain their cognitive enhancing effects. In addition, 5-HT.sub.3 antagonists possess anxiolytic properties, demonstrate potential for use in the treatment of dependency disorders and are under investigation in patients with schizophrenia (see article from The Lancet previously cited).
There is evidence that 5-HT.sub.3 receptors mediate nociceptive input to afferent neurons (see Glaum, S., Proudfit, H. K., and Anderson, E. G.; Neurosci. Lett. 1988; 95:313). 5-HT.sub.3 antagonists may therefore be of value in the control of pain, particularly migraine (see Peatfield R.; Drugs and the Treatment of Migraine. Trends Pharmacol. Sci. 1988; 9:141).
The 5-HT.sub.3 receptor antagonist ICS 205-930 inhibits arrhythmias in a variety of animal models and exerts mixed class III and class I antiarrhythmic properties in ventricular myocytes (see Schlltysik, G. Imoto, Y., Yatani, A. and Brown, A. M.; J. Pharmacol. Exp. Ther. 1988; 245:773 and references therein). 5-HT.sub.3 antagonists may therefore be of use in treating or preventing arrhythmias.
U.S. Pat. No. 5,202,333 describes certain tricyclic compounds with 5-HT.sub.3 receptor antagonist properties. Included among the tricyclic 5-HT.sub.3 receptor antagonists described in U.S. Pat. No. 5,202,333 are (1-azabicyclo[2.2.2]oct-3S-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinol in-1-one and 2-(1-azabicyclo[2.2.2]oct-3S-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin -1-one and it is now known that 2-(1-azabicyclo[2.2.2]oct-3S-yl)-6-hydroxy-2,3,3a,4,5,6-hexahydro-1H-benz[ de]isoquinoline-1-one and 2-(1-azabicyclo[2.2.2]oct-3S-yl)-6-hydroxy-2,4,5,6-tetrahydro-1H-benz[de]i soquinolin-1-one, respectively, are human metabolites thereof.